HCN channels contribute to many vital biological processes and possibly several disease states. But very little is known about the mechanisms of regulation that contribute to its wide range of activation in native tissues. A thorough understanding of these mechanisms could lead to new, tissue-specific therapeutic targets as well as new insights into processes such as transition between states of consciousness and pace making in the heart. We have shown that two HCN isoforms can be modulated by the PTK inhibitor genistein and at least one isoform is a phosphotyrosine protein in vivo. We propose to further investigate the possible tyrosine phosphorylation of HCN channels by determining the sites of mechanistic importance of the genistein response and tyrosine phosphorylation, and probing the interaction between this form of modulation and that which occurs by cyclic nucleotides.